SUMMARY Columbus, Ohio is experiencing a syphilis epidemic comparable to many cities across the United States. In Columbus, primary and secondary syphilis cases have more than doubled since 2011. Cases are concentrated in men who have sex with men (MSM). Most cases are among young black MSM under 35 years, but white MSM, especially those aged 35-54 years, also experience significant morbidity. To address this epidemic, we have assembled an outstanding team of investigators and consultants with expertise in epidemiology, behavioral research, clinical management, and network and spatial analyses. Our specific aims are: 1) To conduct formative research to inform recruitment and data collection procedures among MSM in Columbus; 2) To assess the relative contributions of sex partner types, such as online/anonymous, venue-based, social peers, and travelers, to syphilis incidence in Columbus; 3) To assess the spatiotemporal social and sexual network patterns of syphilis transmission in Columbus. In the formative phase (Aim 1), we will use focus groups and in-depth interviews to determine the ideal characteristics of seeds for respondent-driven sampling (RDS) and to assess other characteristics of the MSM community in Columbus. In this phase, we will also develop a predictive model to inform targeted recruitment of MSM at high-risk for reinfection with Treponema pallidum. To accomplish Aims 2 and 3, we will conduct two parallel studies with supplemental network and spatial analyses. One approach will use a prospective cohort of MSM recruited through RDS (n=300) supplemented by an additional sample of MSM at high risk of reinfection (n=60). All cohort participants will be followed with quarterly interviews and testing for syphilis, gonorrhea, chlamydia, and HIV. Behavioral data collection will be augmented with ecological momentary assessment (EMA) with both open (available at any time) and weekly surveys. The primary endpoint will be primary or secondary syphilis. The second approach will use a case cohort study design, a modern epidemiological approach that increases power for rare diseases such as syphilis. In this approach, the cohort serves as a representative sample of high risk MSM, but cases are supplemented with additional primary and secondary syphilis cases from consenting MSM cases identified in the community. The case cohort design will be used to conduct analyses addressing risk factors for syphilis acquisition. We will also conduct extensive network analyses that incorporate information about partnership duration and continuation using syphilis case data from throughout the community, combined with RDS information, partners services data, detailed sexual partner information, social media and app use, and venue visitation data. We will also examine the epidemic with spatiotemporal analyses, including overlaying network and spatial information. Upon completion of this study, we will have developed an actionable understanding of syphilis epidemiology in a Midwestern city with a large MSM population. Our results will permit development of targeted, scalable interventions directed toward controlling this epidemic.